DESCRIPTION: (Verbatim from the Applicant's Abstract) Transient cerebral ischemia, produced by cardiac arrest, cardiopulmonary bypass surgery, etc., causes neuronal death in selectively vulnerable regions of the brain such as area CA1 of the hippocampus. There exists considerable evidence that glutamate neurotransmission plays an important role in ischemia-induced neuronal death. In contrast, relatively little is known about the role of GABA neurotransmission. The long-term objectives of this research program are to understand the role of GABA neurotransmission in ischemia-induced neuronal death; the major working hypothesis is as follows: GABA neurotransmission is reduced early after ischemia and this may be due, in part, to the generation of reactive oxygen species. The decrease in GABA neurotransmission may promote proapoptotic and other injury signals that eventually lead to neuronal death. Pharmacologic enhancement of GABA neurotransmission early after ischemia may prevent the loss of GABA neurotransmission and generation of early signals of neuronal injury. Both in vivo and in vitro models of ischemia will be used for these studies, in combination of the acutely prepared hippocampal slice. The Specific Aims of the research are to: l) determine the effect of transient cerebral ischemia (in vivo) on GABA neurotransmission within the hippocampal slice, 2) determine the role of oxidative stress in ischemia-induced changes in GABAA responses in the hippocampal slice, 3) determine the potential mechanisms by which oxidative stress (i.e. H2O2) affects GABAA responses in the hippocampal slice and 4) determine the effect of increasing GABA neurotransmission on early injury signals following ischemia in vivo and in vitro. GABAA responses will be measured in differentially-vulnerable areas of the hippocampus including CAl pyramidal neurons, CA1' interneurons and CA4 interneurons using a Cl- sensitive fluorescent dye, MEQ, and W laser scanning confocal microscopy. Perforated patch recordings of area CA 1 pyramidal neurons will provide additional information about changes in the Cl- gradient. Early markers of cell injury will be assessed along with the measurement of GAB4A responses. These markers provide biochemical, structural and functional information concerning neuronal viability. They include, c-fos and MAP2 expression, the proapoptotic signals, cytochrome c efflux and caspase-3 activation, and ATP levels. Understanding how ischemic insults affect inhibitory neuronal transmission and how specific populations of neurons die will help us to identify new treatment strategies to prevent ischemia-induced neuronal death in humans.